PET imaging studies measuring the change in dopamine D2-class of receptors function have historically used radiotracers that are not capable of discriminating between D2/ and D3 receptors. For example, [11C] raclopride, [18F] fallypride and [11C] PHNO bind with high affinity to dopamine D2 and D3 receptors. Therefore, measurement of "D2 receptor binding potential" obtained with these radiotracers consists of a composite of D2 and D3 receptor density. A number of studies have provided evidence suggesting that D2 and D3 receptors are regulated in an opposing manner in a variety of CNS disorders. For example, it has been reported that there is a 45% reduction in D3 receptors in the ventral striatum and a 15% increase in D2 receptors the caudate/putamen of postmortem brain samples of Parkinson's Disease. Other studies have shown an increase in D3 receptors and a decrease in D2 receptors in brain samples obtained following chronic exposure to cocaine. Therefore, the development of radiotracers having a high affinity for D3 versus D2 receptors, and vice versa, would be of tremendous interest to the PET imaging and neuroscience research community since it would enable the independent measurement of D2 and D3 receptors in a variety of CNS disorders. Our group is currently funded (through PA-03-112) to develop PET radiotracers having a high affinity and selectivity for D2 versus D3 receptors. The function of the current research project is to develop PET radiotracers selective for the D3 receptor which would complement our ongoing research in the development of D2-selective radiotracers. The ultimate goal of our research effort is to develop a novel strategy for imaging the change in D3 and D2 receptors in a variety of CNS disorders. PUBLIC HEALTH RELEVANCE: An alteration in the function of the dopamine D3 receptor is thought to play a key role in a variety of pathological conditions including schizophrenia, Parkinson's Disease, Alzheimer's Disease, and drug abuse. However, the precise role of this receptor in these brain disorders is currently not known. The goal of the research described in this grant is to develop novel probes for imaging the D3 receptor in the living human brain with the functional imaging technique Positron Emission Tomography or PET. These probes are expected to provide valuable information on the role of the D3 receptor in disorders of the central nervous system.